Stimulant abuse (e.g. cocaine and methamphetamine) is a major public health problem in the United States. The abuse of CMS stimulants potentiates the impact and progression of HIV-1, hepatitis B and C, and drug resistant tuberculosis. A large body of evidence indicates that kappa opioid receptors may be involved in the modulation of some abuse related effects of CNS stimulants. Thus, kappa opioid receptors offer a pharmacological target to treat stimulant abuse and its attendant pathology, as well as, various types of pain. Kappa opioid receptors have also been implicated in the actions of Salvia divinorum, a hallucinogenic mint plant that is currently unscheduled and readily available to the public over the Internet. Due to the recent increase in the popularity of Salvia divinorum among both European and American teens, the DEA has recently placed it on the list of drugs to watch. It is predictable that its misuse will increase rapidly. In addition, few studies have been conducted on the pharmacological mode of action of Salvia divinorum or its active component, salvinorin A. The central hypothesis of this proposal is that structural modification of salvinorin A will lead to identification of novel kappa opioid receptor ligands with the potential to treat drug dependence and its relapse. The long-term goal of this research is to more fully understand the role of kappa opioid receptor function in treating drug dependence, as well as in hallucinogenic-like activity. The specific aims of this proposal are (1) identify novel ligands for kappa opioid receptors based on the structure of the natural product salvinorin A and (2) identify the role of structural conformation on salvinorin A's affinity and activity. The innovative approach employed in this proposal utilizes medicinal chemistry, in vitro pharmacology and in vivo pharmacology to achieve our goals. This proposal represents a new template for the study of kappa opioid receptors ligands in drug dependence and analgesia.